Vanderbilt University School of Medicine

Osheroff, Neil , Ph.D.
Professor of Biochemistry
John Coniglio Chair in Biochemistry
Professor of Medicine

Lab Url: N/A

Phone Number: 615-322-4338

Email Address:neil.osheroff@vanderbilt.edu

Osheroff, Neil's picture

Office Address   Mailing Address

654 Robinson Research Building

Department of Biochemistry Vanderbilt University School of Medicine 37232-0146


Research Specialty
Function and biology of DNA topoisomerases

Research Description
The intertwining of the two strands of the DNA helix presents a number of topological problems that the cell must be able to overcome in order to maintain its genetic information. Consequently, the enzymes that modulate the topological state of nucleic acids play a crucial role in controlling the physiological functions of DNA.

In the cell, the topological structure of DNA is modulated by ubiquitous enzymes known as topoisomerases. The type II enzyme alters nucleic acid topology by passing an intact double helix of DNA through a transient double-stranded break made in a second DNA helix. In vivo, it is involved in DNA replication, recombination, and chromosome segregation. In addition, topoisomerase II plays important roles in chromosome structure. Beyond its normal cellular activities, the enzyme is the primary target for some of the most active drugs currently used for the treatment of human cancers. Despite the importance of topoisomerase II to the eukaryotic cell and to cancer chemotherapy, there is relatively little understood about its mechanism of action or those of topoisomerase II-targeted drugs.


The goal of my laboratory is to define the function and biology of eukaryotic topoisomerase II. To this end, four broad-based projects are currently underway. First, the enzymatic mechanism, active sites, and structure of topoisomerase II are being characterized. Current studies have delineated a number of individual steps in the catalytic cycle of the enzyme. Second, the mechanism by which chemotherapeutic drugs act on topoisomerase II is being explored. Work in this area has contributed to our understanding of drug action and also has identified at least two novel classes of potential anticancer agents. Third, the mechanism(s) by which topoisomerase II becomes resistant or hypersensitive to anticancer drugs is being addressed. In support of this project, a number of mutant type II topoisomerases with altered drug sensitivity have been isolated and are being characterized. Fourth, interactions between topoisomerase II and DNA lesions are being investigated. Initial work indicates that the enzyme interacts with specific forms of DNA damage and that lesions alter topoisomerase II activity in a manner similar to that of anticancer drugs. These findings indicate a novel physiological function for topoisomerase II and a mechanism by which the enzyme can selectively remove damaged cells from a population. Furthermore, it provides a teleological thread that links the chemotherapeutic actions of clinically relevant anticancer drugs to a natural cellular process.

Publications
Bandele, OJ, Osheroff, N. (-)-Epigallocatechin gallate, a major constituent of green tea, poisons human type II topoisomerases. Chem Res Toxicol, 21(4), 936-43, 2008.

Bender, RP, Jablonksy, MJ, Shadid, M, Romaine, I, Dunlap, N, Anklin, C, Graves, DE, Osheroff, N. Substituents on etoposide that interact with human topoisomerase IIalpha in the binary enzyme-drug complex: contributions to etoposide binding and activity. Biochemistry, 47(15), 4501-9, 2008. PMCID:2737519

Deweese, JE, Burgin, AB, Osheroff, N. Using 3''-bridging phosphorothiolates to isolate the forward DNA cleavage reaction of human topoisomerase IIalpha. Biochemistry, 47(13), 4129-40, 2008. PMCID:2733888

Deweese, JE, Burgin, AB, Osheroff, N. Human topoisomerase II{alpha} uses a two-metal-ion mechanism for DNA cleavage. Nucleic Acids Res, , , 2008. PMCID:2528187

Pilarski, PP, Alan Johnstone, D, Pettepher, CC, Osheroff, N. From music to macromolecules: using rich media/podcast lecture recordings to enhance the preclinical educational experience. Med Teach, 30(6), 630-2, 2008.

Wang, Y, Azuma, Y, Moore, D, Osheroff, N, Neufeld, KL. Interaction between Tumor Suppressor APC and Topoisomerase II{alpha}: Implication for the G2/M Transition. Mol Biol Cell, , , 2008. PMCID:2555924

Bandele, OJ, Osheroff, N. Bioflavonoids as poisons of human topoisomerase II alpha and II beta. Biochemistry, 46(20), 6097-108, 2007.

Bender, RP, Ham, AJ, Osheroff, N. Quinone-Induced Enhancement of DNA Cleavage by Human Topoisomerase IIalpha: Adduction of Cysteine Residues 392 and 405. Biochemistry, 46(10), 2856-64, 2007.

Bender, RP, Osheroff, N. Mutation of cysteine residue 455 to alanine in human topoisomerase IIalpha confers hypersensitivity to quinones: enhancing DNA scission by closing the N-terminal protein gate. Chem Res Toxicol, 20(6), 975-81, 2007.

Fr??hlich, RF, Veigaard, C, Andersen, FF, McClendon, AK, Gentry, AC, Andersen, AH, Osheroff, N, Stevnsner, T, Knudsen, BR. Tryptophane-205 of human topoisomerase I is essential for camptothecin inhibition of negative but not positive supercoil removal. Nucleic Acids Res, 35(18), 6170-80, 2007. PMCID:2094083

McClendon, AK, Osheroff, N. DNA topoisomerase II, genotoxicity, and cancer. Mutat Res, 623(1-2), 83-97, 2007. PMCID:2679583

Wilstermann, AM, Bender, RP, Godfrey, M, Choi, S, Anklin, C, Berkowitz, DB, Osheroff, N, Graves, DE. Topoisomerase II - drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Biochemistry, 46(28), 8217-25, 2007.

Bender, RP, Lehmler, HJ, Robertson, LW, Ludewig, G, Osheroff, N. Polychlorinated biphenyl quinone metabolites poison human topoisomerase IIalpha: altering enzyme function by blocking the N-terminal protein gate. Biochemistry, 45(33), 10140-52, 2006.

Duca, M, Guianvarc''h, D, Oussedik, K, Halby, L, Garbesi, A, Dauzonne, D, Monneret, C, Osheroff, N, Giovannangeli, C, Arimondo, PB. Molecular basis of the targeting of topoisomerase II-mediated DNA cleavage by VP16 derivatives conjugated to triplex-forming oligonucleotides. Nucleic Acids Res, 34(6), 1900-11, 2006. PMCID:1447649

Felix, CA, Kolaris, CP, Osheroff, N. Topoisomerase II and the etiology of chromosomal translocations. DNA Repair (Amst), 5(9-10), 1093-108, 2006.

McClendon, AK, Dickey, JS, Osheroff, N. Ability of viral topoisomerase II to discern the handedness of supercoiled DNA: bimodal recognition of DNA geometry by type II enzymes. Biochemistry, 45(38), 11674-80, 2006. PMCID:2517260

McClendon, AK, Osheroff, N. The geometry of DNA supercoils modulates topoisomerase-mediated DNA cleavage and enzyme response to anticancer drugs. Biochemistry, 45(9), 3040-50, 2006. PMCID:2517258

Osheroff, N. Unraveling the structure of the variola topoisomerase IB-DNA complex: a possible new twist on smallpox therapy. Mol Interv, 6(5), 245-8, 2006.

Baldwin, EL, Berger, AC, Corbett, AH, Osheroff, N. Mms22p protects Saccharomyces cerevisiae from DNA damage induced by topoisomerase II. Nucleic Acids Res, 33(3), 1021-30, 2005. PMCID:549411

Baldwin, EL, Osheroff, N. Etoposide, topoisomerase II and cancer. Curr Med Chem Anti-Canc Agents, 5(4), 363-72, 2005.

Dickey, JS, Choi, TJ, Van Etten, JL, Osheroff, N. Chlorella virus Marburg topoisomerase II: high DNA cleavage activity as a characteristic of Chlorella virus type II enzymes. Biochemistry, 44(10), 3899-908, 2005.

Dickey, JS, Osheroff, N. Impact of the C-terminal domain of topoisomerase IIalpha on the DNA cleavage activity of the human enzyme. Biochemistry, 44(34), 11546-54, 2005. PMCID:2678941

Dickey, JS, Van Etten, JL, Osheroff, N. DNA Methylation Impacts the Cleavage Activity of Chlorella Virus Topoisomerase II. Biochemistry, 44(46), 15378-15386, 2005.

Lindsey, RH, Bender, RP, Osheroff, N. Effects of benzene metabolites on DNA cleavage mediated by human topoisomerase II alpha: 1,4-hydroquinone is a topoisomerase II poison. Chem Res Toxicol, 18(4), 761-70, 2005.

Lindsey, RH, Bender, RP, Osheroff, N. Stimulation of topoisomerase II-mediated DNA cleavage by benzene metabolites. Chem Biol Interact, 153-154, 197-205, 2005.

McClendon, AK, Rodriguez, AC, Osheroff, N. Human topoisomerase IIalpha rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. J Biol Chem, 280(47), 39337-45, 2005.

Mistry, AR, Felix, CA, Whitmarsh, RJ, Mason, A, Reiter, A, Cassinat, B, Parry, A, Walz, C, Wiemels, JL, Segal, MR, Ad??s, L, Blair, IA, Osheroff, N, Peniket, AJ, Lafage-Pochitaloff, M, Cross, NC, Chomienne, C, Solomon, E, Fenaux, P, Grimwade, D. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med, 352(15), 1529-38, 2005.

V??lez-Cruz, R, Riggins, JN, Daniels, JS, Cai, H, Guengerich, FP, Marnett, LJ, Osheroff, N. Exocyclic DNA lesions stimulate DNA cleavage mediated by human topoisomerase II alpha in vitro and in cultured cells. Biochemistry, 44(10), 3972-81, 2005.

Baldwin, Erin L, Byl, Jo Ann Wilson, Osheroff, Neil. Cobalt enhances DNA cleavage mediated by human topoisomerase IIalpha in vitro and in cultured cells. Biochemistry, 43(3), 728-35, 2004.

Bender, Ryan P, Lindsey, R Hunter, Burden, D Andrew, Osheroff, Neil. N-Acetyl-p-benzoquinone Imine, the Toxic Metabolite of Acetaminophen, Is a Topoisomerase II Poison. Biochemistry, 43(12), 3731-9, 2004.

Bromberg, KD, V??lez-Cruz, R, Burgin, AB, Osheroff, N. DNA ligation catalyzed by human topoisomerase II alpha. Biochemistry, 43(42), 13416-23, 2004.

D.S. Sappal, A.K. McClendon, J.A. Fleming, V. Thoroddsen, K. Connolly, C. Reimer, R.K. Blackman, C.E. Bulawa, N. Osheroff, P. Charlton, and L.A. Rudolph-Owen . Biological Characterization of MLN944; A Potent DNA Binding Agent. Mol. Cancer. Ther., (3), 47-58, 2004.

Lindsey, RH, Bromberg, KD, Felix, CA, Osheroff, N. 1,4-Benzoquinone is a topoisomerase II poison. Biochemistry, 43(23), 7563-74, 2004.

Osheroff, Neil. Diflomotecan. IDrugs, 7(3), 257-63, 2004.

R. Velez-Cruz, and N. Osheroff . Topoisomerases: Eukaryotic and Prokaryotic Type II. Encyclopedia of Molecular Biology (W. Lennarz, and M.D. Lane, eds.) Elsevier Science, San Diego, in press., 1, 806-811, 2004.

Sappal, DS, McClendon, AK, Fleming, JA, Thoroddsen, V, Connolly, K, Reimer, C, Blackman, RK, Bulawa, CE, Osheroff, N, Charlton, P, Rudolph-Owen, LA. Biological characterization of MLN944: a potent DNA binding agent. Mol Cancer Ther, 3(1), 47-58, 2004.

Bromberg, Kenneth D, Burgin, Alex B, Osheroff, Neil. A two-drug model for etoposide action against human topoisomerase IIalpha. J Biol Chem, 278, 7406-12, 2003.

Bromberg, Kenneth D, Burgin, Alex B, Osheroff, Neil. Quinolone action against human topoisomerase IIalpha: stimulation of enzyme-mediated double-stranded DNA cleavage. Biochemistry, 42, 3393-8, 2003.

M?Yrtensson, S, Nygren, J, Osheroff, N, Hammarsten, O. Activation of the DNA-dependent protein kinase by drug-induced and radiation-induced DNA strand breaks. Radiat Res, 160(3), 291-301, 2003.

S. Martensson, J. Nygren, N. Osheroff, and O. Hammarsten. Activation of DNA-dependent PRotein Kinase by Drug and Radiation-induced DNA Strand Breaks. Radiation Res., (160), 291-301, 2003.

Sabourin, Michelle, Nitiss, John L, Nitiss, Karin C, Tatebayashi, Kazuo, Ikeda, Hideo, Osheroff, Neil. Yeast recombination pathways triggered by topoisomerase II-mediated DNA breaks. Nucleic Acids Res, 31, 4373-84, 2003. PMCID:169887

Whitmarsh, RJ, Saginario, C, Zhuo, Y, Hilgenfeld, E, Rappaport, EF, Megonigal, MD, Carroll, M, Liu, M, Osheroff, N, Cheung, NK, Slater, DJ, Ried, T, Knutsen, T, Blair, IA, Felix, CA. Reciprocal DNA topoisomerase II cleavage events at 5''-TATTA-3'' sequences in MLL and AF-9 create homologous single-stranded overhangs that anneal to form der(11) and der(9) genomic breakpoint junctions in treatment-related AML without further processing. Oncogene, 22(52), 8448-59, 2003.

Wilstermann, Amy M, Osheroff, Neil. Stabilization of eukaryotic topoisomerase II-DNA cleavage complexes. Curr Top Med Chem, 3, 321-38, 2003.

Bromberg, Kenneth D, Hendricks, Chris, Burgin, Alex B, Osheroff, Neil. Human topoisomerase IIalpha possesses an intrinsic nucleic acid specificity for DNA ligation. Use of 5' covalently activated oligonucleotide substrates to study enzyme mechanism. J Biol Chem, 277, 31201-6, 2002.

Fortune, John M, Dickey, Jennifer S, Lavrukhin, Oleg V, Van Etten, James L, Lloyd, R Stephen, Osheroff, Neil. Site-specific DNA cleavage by Chlorella virus topoisomerase II. Biochemistry, 41, 11761-9, 2002.

Morrison, Ciaran, Henzing, Alexander J, Jensen, Ole N??rregaard, Osheroff, Neil, Dodson, Helen, Kandels-Lewis, Stefanie E, Adams, Richard R, Earnshaw, William C. Proteomic analysis of human metaphase chromosomes reveals topoisomerase II alpha as an Aurora B substrate. Nucleic Acids Res, 30, 5318-27, 2002. PMCID:137976

Slater, Diana J, Hilgenfeld, Eva, Rappaport, Eric F, Shah, Narayan, Meek, Rita G, Williams, Wendy Reed, Lovett, Brian D, Osheroff, Neil, Autar, Reshma S, Ried, Thomas, Felix, Carolyn A. MLL-SEPTIN6 fusion recurs in novel translocation of chromosomes 3, X, and 11 in infant acute myelomonocytic leukaemia and in t(X;11) in infant acute myeloid leukaemia, and MLL genomic breakpoint in complex MLL-SEPTIN6 rearrangement is a DNA topoisomerase II cleavage site. Oncogene, 21, 4706-14, 2002.

Anderson, V E, Osheroff, N. Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde. Curr Pharm Des, 7, 337-53, 2001.

Bromberg, K D, Osheroff, N. DNA cleavage and religation by human topoisomerase II alpha at high temperature. Biochemistry, 40, 8410-8, 2001.

Burden, D A, Froelich-Ammon, S J, Osheroff, N. Topoisomerase II-mediated cleavage of plasmid DNA. Methods Mol Biol, 95, 283-9, 2001.

Byl, J A, Cline, S D, Utsugi, T, Kobunai, T, Yamada, Y, Osheroff, N. DNA topoisomerase II as the target for the anticancer drug TOP-53: mechanistic basis for drug action. Biochemistry, 40(3), 712-8, 2001.

Fortune, J M, Lavrukhin, O V, Gurnon, J R, Van Etten, J L, Lloyd, R S, Osheroff, N. Topoisomerase II from Chlorella virus PBCV-1 has an exceptionally high DNA cleavage activity. J Biol Chem, 276, 24401-8, 2001.

Fortune, J M, Osheroff, N. Topoisomerase II-catalyzed relaxation and catenation of plasmid DNA. Methods Mol Biol, 95, 275-81, 2001.

J.A.W. Byl, T. Utsugi, T. Kobunai, Y. Yamada, and N. Osheroff . DNA Topoisomerase II as the Target for the Anticancer Drug TOP-53: Mechanistic Basis for Drug Action. Biochemistry, (40), 712-718, 2001.

Kingma, P S, Fortune, J M, Osheroff, N. Topoisomerase II-catalyzed ATP hydrolysis as monitored by thin-layer chromatography. Methods Mol Biol, 95, 51-6, 2001.

Lovett, B D, Lo Nigro, L, Rappaport, E F, Blair, I A, Osheroff, N, Zheng, N, Megonigal, M D, Williams, W R, Nowell, P C, Felix, C A. Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation. Proc Natl Acad Sci U S A, 98, 9802-7, 2001. PMCID:55533

Lovett, B D, Strumberg, D, Blair, I A, Pang, S, Burden, D A, Megonigal, M D, Rappaport, E F, Rebbeck, T R, Osheroff, N, Pommier, Y G, Felix, C A. Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints. Biochemistry, 40, 1159-70, 2001.

V.E. Anderson, and N. Osheroff. Topoisomerase-Targeted Antibacterials: Turning Dr. Jekyll into Mr. Hyde. Curr. Pharm. Design, (7), 339-355, 2001.

Wilstermann, A M, Osheroff, N. Positioning the 3'-DNA terminus for topoisomerase II-mediated religation. J Biol Chem, 276, 17727-31, 2001.

Wilstermann, A M, Osheroff, N. Base excision repair intermediates as topoisomerase II poisons. J Biol Chem, 276, 46290-6, 2001.

Anderson, V E, Zaniewski, R P, Kaczmarek, F S, Gootz, T D, Osheroff, N. Action of quinolones against Staphylococcus aureus topoisomerase IV: basis for DNA cleavage enhancement. Biochemistry, 39(10), 2726-32, 2000.

Bjergbaek, L, Kingma, P, Nielsen, IS, Wang, Y, Westergaard, O, Osheroff, N, Andersen, AH. Communication between the ATPase and cleavage/religation domains of human topoisomerase IIalpha. J Biol Chem, 275(17), 13041-8, 2000.

Durrieu, F, Samejima, K, Fortune, JM, Kandels-Lewis, S, Osheroff, N, Earnshaw, WC. DNA topoisomerase IIalpha interacts with CAD nuclease and is involved in chromatin condensation during apoptotic execution. Curr Biol, 10(15), 923-6, 2000.

Earnshaw, WC, Samejima, K, Durrieu, F, Fortune, J, Osheroff, N. Biochemical mechanism of apoptotic execution. Ann Endocrinol (Paris), 61(2), 137, 2000.

F. Durrieu, K. Samejima, J.M. Fortune, S. Kandels-Lewis, N. Osheroff, and W.C. Earnshaw . Involvement of DNA Topoisomerase II in Chromatin Condensation During Apoptotic Execution. Curr. Biol. (Brief Communication) , (10), 923-926, 2000.

Fortune, J M, Osheroff, N. Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice. Prog Nucleic Acid Res Mol Biol, 64, 221-53, 2000.

J.M. Fortune, and N. Osheroff . "Topoisomerase II as a Target for Anticancer Drugs: When Enzymes Stop Being Nice" . Prog. Nuc. Acid Res. Mol Biol., 64, 221-253, 2000.

Jensen, LH, Nitiss, KC, Rose, A, Dong, J, Zhou, J, Hu, T, Osheroff, N, Jensen, PB, Sehested, M, Nitiss, JL. A novel mechanism of cell killing by anti-topoisomerase II bisdioxopiperazines. J Biol Chem, 275(3), 2137-46, 2000.

Kluza, J, Lansiaux, A, Wattez, N, Mahieu, C, Osheroff, N, Bailly, C. Apoptotic response of HL-60 human leukemia cells to the antitumor drug TAS-103. Cancer Res, 60(15), 4077-84, 2000.

L. Bjergb?k, P. Kingma, I.S. Nielsen, Y. Wong, O. Westergaard, N. Osheroff, and A.H. Andersen. Uncoupling the ATPase and Cleavage/Ligation Activities of Human DNA Topoisomerase IIα by a Deletion in the N-terminal Region. J. Biol. Chem. , (275), 13041-13048, 2000.

L.H. Jensen, K.C. Nitiss, A. Rose, J. Dong, J. Zhou, T. Hu, N. Osheroff, P.B. Jensen, M. Sehested, and J.L. Nitiss . "A Novel Mechanism of Cell Killing by Anti-topoisomerase II Bisdioxopiperazines.". J. Biol. Chem., 275, 2137-2146, 2000.

Lavrukhin, OV, Fortune, JM, Wood, TG, Burbank, DE, Van Etten, JL, Osheroff, N, Lloyd, RS. Topoisomerase II from Chlorella virus PBCV-1. Characterization of the smallest known type II topoisomerase. J Biol Chem, 275(10), 6915-21, 2000.

M. Sabourin, and N. Osheroff . Sensitivity of Human Type II Topoisomerases to DNA Damage: Stimulation of Enzyme-mediated DNA Cleavage by Abasic, Oxidized, and Alkylated Lesions. Nuc. Acids Res., (28), 1947-1954, 2000.

O.V. Lavrukhin, J.M. Fortune, T.G. Wood, D.E. Burbank, J.L. Van Etten, N. Osheroff, and R.S. Lloyd. "Topoisomerase II from Chlorella Virus PBCV-1: Characterization of the Smallest Known Type II Topoisomerase." . J. Biol. Chem., 275, 6915-6921, 2000.

Sabourin, M, Osheroff, N. Sensitivity of human type II topoisomerases to DNA damage: stimulation of enzyme-mediated DNA cleavage by abasic, oxidized and alkylated lesions. Nucleic Acids Res, 28(9), 1947-54, 2000. PMCID:103304

V.E. Anderson, R.P. Zaniewski, F.S. Kaczmarek, T.D. Gootz, and N. Osheroff. "Action of Quinolones Against Staphylococcus aureus Topoisomerase IV: Basis for DNA Cleavage Enhancement" . Biochemistry, 39, 2726-2732, 2000.

Anderson, V E, Zaniewski, R P, Kaczmarek, F S, Gootz, T D, Osheroff, N. Quinolones inhibit DNA religation mediated by Staphylococcus aureus topoisomerase IV. Changes in drug mechanism across evolutionary boundaries. J Biol Chem, 274(50), 35927-32, 1999.

Bjornsti, M A, Osheroff, N. Introduction to DNA topoisomerases. Methods Mol Biol, 94, 1-8, 1999.

Burden, D A, Osheroff, N. In vitro evolution of preferred topoisomerase II DNA cleavage sites. J Biol Chem, 274(8), 5227-35, 1999.

Byl, J A, Fortune, J M, Burden, D A, Nitiss, J L, Utsugi, T, Yamada, Y, Osheroff, N. DNA topoisomerases as targets for the anticancer drug TAS-103: primary cellular target and DNA cleavage enhancement. Biochemistry, 38(47), 15573-9, 1999.

Cline, S D, Jones, W R, Stone, M P, Osheroff, N. DNA abasic lesions in a different light: solution structure of an endogenous topoisomerase II poison. Biochemistry, 38(47), 15500-7, 1999.

Cline, S D, Osheroff, N. Cytosine arabinoside lesions are position-specific topoisomerase II poisons and stimulate DNA cleavage mediated by the human type II enzymes. J Biol Chem, 274(42), 29740-3, 1999.

D.A. Burden, and N. Osheroff. "In Vitro Evolution of Preferred Topoisomerase II DNA Cleavage Sites.". J. Biol. Chem., 274, 5227-5235, 1999.

Fortune, J M, Velea, L, Graves, D E, Utsugi, T, Yamada, Y, Osheroff, N. DNA topoisomerases as targets for the anticancer drug TAS-103: DNA interactions and topoisomerase catalytic inhibition. Biochemistry, 38(47), 15580-6, 1999.

Froelich-Ammon, S J, Kingma, P S, Osheroff, N. Purification of DNA Topoisomerase II from Drosophila melanogaster. Methods Mol Biol, 94, 199-212, 1999.

J.A.W. Byl, J.M. Fortune, D.A. Burden, J.L. Nitiss, T. Utsugi, Y. Yamada, and N. Osheroff. "DNA Topoisomerases as Targets for the Anticancer Drug TAS-103: Primary Cellular Target and DNA Cleavage Enhancement." . Biochemistry, 38, 15573-15579, 1999.

J.M. Fortune, L. Velea, D.E. Graves, T. Utsugi, Y. Yamada, and N. Osheroff. "DNA Topoisomerases as Targets for the Anticancer Drug TAS-103: DNA Interactions and Topoisomerase Catalytic Inhibition.". Biochemistry, 38, 15580-15586, 1999.

Kingma, P S, Burden, D A, Osheroff, N. Binding of etoposide to topoisomerase II in the absence of DNA: decreased affinity as a mechanism of drug resistance. Biochemistry, 38(12), 3457-61, 1999.

P. Shapiro, A.M. Walen, N. Tolwinski, S.J. Froelich-Ammon, M. Garcia, N. Osheroff, and N.G. Ahn . "ERK Activates Topoisomerase II Alpha Through a Mechanism Independent of Phosphorylation." . Molec. Cell. Biol., 19, 3551-3560, 1999.

P.S. Kingma, D.A. Burden, and N. Osheroff. "Binding of Etoposide to Topoisomerase II in the Absence of DNA: Decreased Affinity as a Mechanism of Drug Resistance." . Biochemistry, 38, 3457-3461, 1999.

S.D. Cline, W.R. Jones, M.P. Stone, and N. Osheroff . "DNA Abasic Lesions in a Different Light: Structure of an Endogenous Topoisomerase II Poison." . Biochemistry, 38, 15500 15507, 1999.

S.D. Cline, and N. Osheroff. "Cytosine Arabinoside (AraC) Lesions are Position-Specific Topoisomerase II Poisons and Stimulate DNA Cleavage Mediated by the Human Type II Enzymes." . J. Biol. Chem , 274, 29740-29743, 1999.

Shapiro, PS, Whalen, AM, Tolwinski, NS, Wilsbacher, J, Froelich-Ammon, SJ, Garcia, M, Osheroff, N, Ahn, NG. Extracellular signal-regulated kinase activates topoisomerase IIalpha through a mechanism independent of phosphorylation. Mol Cell Biol, 19(5), 3551-60, 1999. PMCID:84147

V.E. Anderson, R.P. Zaniewski, F.S. Kaczmarek, T.D. Gootz, and N. Osheroff. "Quinolones Inhibit DNA Religation Mediated by Staphylococcus aureus Topoisomerase IV: Changes in Drug Mechanism Across Evolutionary Boundaries." . J. Biol. Chem., 274, 35927-35932, 1999.

Anderson, V E, Gootz, T D, Osheroff, N. Topoisomerase IV catalysis and the mechanism of quinolone action. J Biol Chem, 273(28), 17879-85, 1998.

Burden, D A, Osheroff, N. Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim Biophys Acta, 1400(1-3), 139-54, 1998.

Fortune, J M, Osheroff, N. Merbarone inhibits the catalytic activity of human topoisomerase IIalpha by blocking DNA cleavage. J Biol Chem, 273(28), 17643-50, 1998.

Kingma, P S, Osheroff, N. Topoisomerase II-mediated DNA cleavage and religation in the absence of base pairing. Abasic lesions as a tool to dissect enzyme mechanism. J Biol Chem, 273(29), 17999-8002, 1998.

Kingma, P S, Osheroff, N. The response of eukaryotic topoisomerases to DNA damage. Biochim Biophys Acta, 1400(1-3), 223-32, 1998.

Nitiss, JL, Zhou, J, Rose, A, Hsiung, Y, Gale, KC, Osheroff, N. The bis(naphthalimide) DMP-840 causes cytotoxicity by its action against eukaryotic topoisomerase II. Biochemistry, 37(9), 3078-85, 1998.

Osheroff, N. DNA topoisomerases. Biochim Biophys Acta, 1400(1-3), 1-2, 1998.

Sabourin, M, Byl, J A, Hannah, S E, Nitiss, J L, Osheroff, N. A mutant yeast topoisomerase II (top2G437S) with differential sensitivity to anticancer drugs in the presence and absence of ATP. J Biol Chem, 273(44), 29086-92, 1998.

Cline, S D, Macdonald, T L, Osheroff, N. Azatoxin is a mechanistic hybrid of the topoisomerase II-targeted anticancer drugs etoposide and ellipticine. Biochemistry, 36(42), 13095-101, 1997.

Elsea, S H, Westergaard, M, Burden, D A, Lomenick, J P, Osheroff, N. Quinolones share a common interaction domain on topoisomerase II with other DNA cleavage-enhancing antineoplastic drugs. Biochemistry, 36(10), 2919-24, 1997.

Kingma, P S, Greider, C A, Osheroff, N. Spontaneous DNA lesions poison human topoisomerase IIalpha and stimulate cleavage proximal to leukemic 11q23 chromosomal breakpoints. Biochemistry, 36(20), 5934-9, 1997.

Kingma, P S, Osheroff, N. Spontaneous DNA damage stimulates topoisomerase II-mediated DNA cleavage. J Biol Chem, 272(11), 7488-93, 1997.

Kingma, P S, Osheroff, N. Apurinic sites are position-specific topoisomerase II poisons. J Biol Chem, 272(2), 1148-55, 1997.

Marx, G, Zhou, H, Graves, DE, Osheroff, N. Covalent attachment of ethidium to DNA results in enhanced topoisomerase II-mediated DNA cleavage. Biochemistry, 36(50), 15884-91, 1997.

Burden, D A, Kingma, P S, Froelich-Ammon, S J, Bjornsti, M A, Patchan, M W, Thompson, R B, Osheroff, N. Topoisomerase II.etoposide interactions direct the formation of drug-induced enzyme-DNA cleavage complexes. J Biol Chem, 271(46), 29238-44, 1996.

Elsea, S H, Hsiung, Y, Nitiss, J L, Osheroff, N. A yeast type II topoisomerase selected for resistance to quinolones. Mutation of histidine 1012 to tyrosine confers resistance to nonintercalative drugs but hypersensitivity to ellipticine. J Biol Chem, 270(4), 1913-20, 1995.

Froelich-Ammon, S J, Burden, D A, Patchan, M W, Elsea, S H, Thompson, R B, Osheroff, N. Increased drug affinity as the mechanistic basis for drug hypersensitivity of a mutant type II topoisomerase. J Biol Chem, 270(47), 28018-21, 1995.

Froelich-Ammon, S J, Osheroff, N. Topoisomerase poisons: harnessing the dark side of enzyme mechanism. J Biol Chem, 270(37), 21429-32, 1995.

Froelich-Ammon, S J, Patchan, M W, Osheroff, N, Thompson, R B. Topoisomerase II binds to ellipticine in the absence or presence of DNA. Characterization of enzyme-drug interactions by fluorescence spectroscopy. J Biol Chem, 270(25), 14998-5004, 1995.

Hsiung, Y, Elsea, SH, Osheroff, N, Nitiss, JL. A mutation in yeast TOP2 homologous to a quinolone-resistant mutation in bacteria. Mutation of the amino acid homologous to Ser83 of Escherichia coli gyrA alters sensitivity to eukaryotic topoisomerase inhibitors. J Biol Chem, 270(35), 20359-64, 1995.

Kingma, P S, Corbett, A H, Burcham, P C, Marnett, L J, Osheroff, N. Abasic sites stimulate double-stranded DNA cleavage mediated by topoisomerase II. DNA lesions as endogenous topoisomerase II poisons. J Biol Chem, 270(37), 21441-4, 1995.

Froelich-Ammon, S J, Gale, K C, Osheroff, N. Site-specific cleavage of a DNA hairpin by topoisomerase II. DNA secondary structure as a determinant of enzyme recognition/cleavage. J Biol Chem, 269(10), 7719-25, 1994.

Lin, L H, Van Eldik, L J, Osheroff, N, Norden, J J. Inhibition of protein kinase C- and casein kinase II-mediated phosphorylation of GAP-43 by S100 beta. Brain Res Mol Brain Res, 25(3-4), 297-304, 1994.

Osheroff, N, Corbett, A H, Elsea, S H, Westergaard, M. Defining functional drug-interaction domains on topoisomerase II by exploiting mechanistic differences between drug classes. Cancer Chemother Pharmacol, 34 Suppl, S19-25, 1994.

Osheroff, N, Corbett, A H, Robinson, M J. Mechanism of action of topoisomerase II-targeted antineoplastic drugs. Adv Pharmacol, 29B, 105-26, 1994.

Corbett, A H, Fernald, A W, Osheroff, N. Protein kinase C modulates the catalytic activity of topoisomerase II by enhancing the rate of ATP hydrolysis: evidence for a common mechanism of regulation by phosphorylation. Biochemistry, 32(8), 2090-7, 1993.

Corbett, A H, Guerry, P, Pflieger, P, Osheroff, N. A pyrimido[1,6-a]benzimidazole that enhances DNA cleavage mediated by eukaryotic topoisomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential. Antimicrob Agents Chemother, 37(12), 2599-605, 1993. PMCID:192751

Corbett, A H, Hong, D, Osheroff, N. Exploiting mechanistic differences between drug classes to define functional drug interaction domains on topoisomerase II. Evidence that several diverse DNA cleavage-enhancing agents share a common site of action on the enzyme. J Biol Chem, 268(19), 14394-8, 1993.

Corbett, A H, Osheroff, N. When good enzymes go bad: conversion of topoisomerase II to a cellular toxin by antineoplastic drugs. Chem Res Toxicol, 6(5), 585-97, 1993.

Elsea, S H, McGuirk, P R, Gootz, T D, Moynihan, M, Osheroff, N. Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential. Antimicrob Agents Chemother, 37(10), 2179-86, 1993. PMCID:192247

Froelich-Ammon, S J, McGuirk, P R, Gootz, T D, Jefson, M R, Osheroff, N. Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme. Antimicrob Agents Chemother, 37(4), 646-51, 1993. PMCID:187729

Kroeger, PE, Osheroff, N, Rowe, TC. Analysis of topoisomerase II-mediated DNA cleavage in the 5''-region of the Drosophila hsp70 gene. Identification of a novel half-site DNA substrate for topoisomerase II cleavage. J Biol Chem, 268(22), 16449-57, 1993.

Robinson, M J, Corbett, A H, Osheroff, N. Effects of topoisomerase II-targeted drugs on enzyme-mediated DNA cleavage and ATP hydrolysis: evidence for distinct drug interaction domains on topoisomerase II. Biochemistry, 32(14), 3638-43, 1993.

Corbett, A H, DeVore, R F, Osheroff, N. Effect of casein kinase II-mediated phosphorylation on the catalytic cycle of topoisomerase II. Regulation of enzyme activity by enhancement of ATP hydrolysis. J Biol Chem, 267(28), 20513-8, 1992.

Corbett, A H, Zechiedrich, E L, Osheroff, N. A role for the passage helix in the DNA cleavage reaction of eukaryotic topoisomerase II. A two-site model for enzyme-mediated DNA cleavage. J Biol Chem, 267(2), 683-6, 1992.

DeVore, R F, Corbett, A H, Osheroff, N. Phosphorylation of topoisomerase II by casein kinase II and protein kinase C: effects on enzyme-mediated DNA cleavage/religation and sensitivity to the antineoplastic drugs etoposide and 4'-(9-acridinylamino)methane-sulfon-m-anisidide. Cancer Res, 52(8), 2156-61, 1992.

Elsea, S H, Osheroff, N, Nitiss, J L. Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast. J Biol Chem, 267(19), 13150-3, 1992.

Gale, K C, Osheroff, N. Intrinsic intermolecular DNA ligation activity of eukaryotic topoisomerase II. Potential roles in recombination. J Biol Chem, 267(17), 12090-7, 1992.

Robinson, M J, Martin, B A, Gootz, T D, McGuirk, P R, Osheroff, N. Effects of novel fluoroquinolones on the catalytic activities of eukaryotic topoisomerase II: Influence of the C-8 fluorine group. Antimicrob Agents Chemother, 36(4), 751-6, 1992. PMCID:189387

Corbett, A H, Zechiedrich, E L, Lloyd, R S, Osheroff, N. Inhibition of eukaryotic topoisomerase II by ultraviolet-induced cyclobutane pyrimidine dimers. J Biol Chem, 266(29), 19666-71, 1991.

Osheroff, N, Zechiedrich, E L, Gale, K C. Catalytic function of DNA topoisomerase II. Bioessays, 13(6), 269-73, 1991.

Robinson, M J, Martin, B A, Gootz, T D, McGuirk, P R, Moynihan, M, Sutcliffe, J A, Osheroff, N. Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage. J Biol Chem, 266(22), 14585-92, 1991.

Robinson, M J, Osheroff, N. Effects of antineoplastic drugs on the post-strand-passage DNA cleavage/religation equilibrium of topoisomerase II. Biochemistry, 30(7), 1807-13, 1991.

Ackerman, P, Glover, C V, Osheroff, N. Stimulation of casein kinase II by epidermal growth factor: relationship between the physiological activity of the kinase and the phosphorylation state of its beta subunit. Proc Natl Acad Sci U S A, 87(2), 821-5, 1990. PMCID:53358

Gale, K C, Osheroff, N. Uncoupling the DNA cleavage and religation activities of topoisomerase II with a single-stranded nucleic acid substrate: evidence for an active enzyme-cleaved DNA intermediate. Biochemistry, 29(41), 9538-45, 1990.

Robinson, M J, Osheroff, N. Stabilization of the topoisomerase II-DNA cleavage complex by antineoplastic drugs: inhibition of enzyme-mediated DNA religation by 4'-(9-acridinylamino)methanesulfon-m-anisidide. Biochemistry, 29(10), 2511-5, 1990.

Zechiedrich, E L, Osheroff, N. Eukaryotic topoisomerases recognize nucleic acid topology by preferentially interacting with DNA crossovers. EMBO J, 9(13), 4555-62, 1990. PMCID:552253

Ackerman, P, Osheroff, N. Regulation of casein kinase II activity by epidermal growth factor in human A-431 carcinoma cells. J Biol Chem, 264(20), 11958-65, 1989.

Andersen, AH, Christiansen, K, Zechiedrich, EL, Jensen, PS, Osheroff, N, Westergaard, O. Strand specificity of the topoisomerase II mediated double-stranded DNA cleavage reaction. Biochemistry, 28(15), 6237-44, 1989.

Osheroff, N. Effect of antineoplastic agents on the DNA cleavage/religation reaction of eukaryotic topoisomerase II: inhibition of DNA religation by etoposide. Biochemistry, 28(15), 6157-60, 1989.

Osheroff, N. Biochemical basis for the interactions of type I and type II topoisomerases with DNA. Pharmacol Ther, 41(1-2), 223-41, 1989.

Zechiedrich, E L, Christiansen, K, Andersen, A H, Westergaard, O, Osheroff, N. Double-stranded DNA cleavage/religation reaction of eukaryotic topoisomerase II: evidence for a nicked DNA intermediate. Biochemistry, 28(15), 6229-36, 1989.

Ackerman, P, Glover, C V, Osheroff, N. Phosphorylation of DNA topoisomerase II in vivo and in total homogenates of Drosophila Kc cells. The role of casein kinase II. J Biol Chem, 263(25), 12653-60, 1988.

Osheroff, N. Role of the divalent cation in topoisomerase II mediated reactions. Biochemistry, 26(20), 6402-6, 1987.

Osheroff, N, Zechiedrich, E L. Calcium-promoted DNA cleavage by eukaryotic topoisomerase II: trapping the covalent enzyme-DNA complex in an active form. Biochemistry, 26(14), 4303-9, 1987.

Armstrong, GD, Chapman, SK, Sisley, MJ, Sykes, AG, Aitken, A, Osheroff, N, Margoliash, E. Preferred sites on cytochrome c for electron transfer with two positively charged blue copper proteins, Anabaena variabilis plastocyanin and stellacyanin. Biochemistry, 25(22), 6947-51, 1986.

Osheroff, N. Eukaryotic topoisomerase II. Characterization of enzyme turnover. J Biol Chem, 261(21), 9944-50, 1986.

Ackerman, P, Glover, CV, Osheroff, N. Phosphorylation of DNA topoisomerase II by casein kinase II: modulation of eukaryotic topoisomerase II activity in vitro. Proc Natl Acad Sci U S A, 82(10), 3164-8, 1985. PMCID:397735

Berrios, M, Osheroff, N, Fisher, PA. In situ localization of DNA topoisomerase II, a major polypeptide component of the Drosophila nuclear matrix fraction. Proc Natl Acad Sci U S A, 82(12), 4142-6, 1985. PMCID:397951

Guyer, CA, Morgan, DG, Osheroff, N, Staros, JV. Purification and characterization of a periplasmic oligopeptide binding protein from Escherichia coli. J Biol Chem, 260(19), 10812-8, 1985.

Butler, J, Chapman, SK, Davies, DM, Sykes, AG, Speck, SH, Osheroff, N, Margoliash, E. Preferred sites for electron transfer between cytochrome c and iron and cobalt complexes. J Biol Chem, 258(10), 6400-4, 1983.

Osheroff, N, Shelton, ER, Brutlag, DL. DNA topoisomerase II from Drosophila melanogaster. Relaxation of supercoiled DNA. J Biol Chem, 258(15), 9536-43, 1983.

Osheroff, N, Speck, SH, Margoliash, E, Veerman, EC, Wilms, J, K??nig, BW, Muijsers, AO. The reaction of primate cytochromes c with cytochrome c oxidase. Analysis of the polarographic assay. J Biol Chem, 258(9), 5731-8, 1983.

Shelton, ER, Osheroff, N, Brutlag, DL. DNA topoisomerase II from Drosophila melanogaster. Purification and physical characterization. J Biol Chem, 258(15), 9530-5, 1983.

Veerman, EC, Wilms, J, Dekker, HL, Muijsers, AO, van Buuren, KJ, van Gelder, BF, Osheroff, N, Speck, SH, Margoliash, E. The presteady state reaction of chemically modified cytochromes c with cytochrome oxidase. J Biol Chem, 258(9), 5739-45, 1983.

Speck, SH, Koppenol, WH, Dethmers, JK, Osheroff, N, Margoliash, E, Rajagopalan, KV. Definition of cytochrome c binding domains by chemical modification. Interaction of horse cytochrome c with beef sulfite oxidase and analysis of steady state kinetics. J Biol Chem, 256(14), 7394-400, 1981.

K??nig, BW, Osheroff, N, Wilms, J, Muijsers, AO, Dekker, HL, Margoliash, E. Mapping of the interaction domain for purified cytochrome c1 on cytochrome c. FEBS Lett, 111(2), 395-8, 1980.

Osheroff, N, Borden, D, Koppenol, WH, Margoliash, E. Electrostatic interactions in cytochrome c. The role of interactions between residues 13 and 90 and residues 79 and 47 in stabilizing the heme crevice structure. J Biol Chem, 255(4), 1689-97, 1980.

Osheroff, N, Brautigan, DL, Margoliash, E. Definition of enzymic interaction domains on cytochrome c. Purification and activity of singly substituted carboxydinitrophenyl-lysine 7, 25, 73, 86, and 99 cytochromes c. J Biol Chem, 255(17), 8245-51, 1980.

Osheroff, N, Brautigan, DL, Margoliash, E. Mapping of anion binding sites on cytochrome c by differential chemical modification of lysine residues. Proc Natl Acad Sci U S A, 77(8), 4439-43, 1980. PMCID:349859

Osheroff, N, Jemmerson, R, Speck, SH, Ferguson-Miller, S, Margoliash, E. Site-specific anti-cytochrome c antibodies. Inhibition of the reactions between cytochrome c and its respiratory chain electron exchange partners. J Biol Chem, 254(24), 12717-24, 1979.

Speck, SH, Ferguson-Miller, S, Osheroff, N, Margoliash, E. Definition of cytochrome c binding domains by chemical modification: kinetics of reaction with beef mitochondrial reductase and functional organization of the respiratory chain. Proc Natl Acad Sci U S A, 76(1), 155-9, 1979. PMCID:382895

Kang, CH, Brautigan, DL, Osheroff, N, Margoliash, E. Definitaion of cytochrome c binding domains by chemical modification. Reaction of carboxydinitrophenyl- and trinitrophenyl-cytochromes c with baker''s yeast cytochrome c peroxidase. J Biol Chem, 253(18), 6502-10, 1978.

Osheroff, N, Feinberg, BA, Margoliash, E, Morrison, M. Lactoperoxidase-catalyzed iodination of horse cytochrome c:monoiodotyrosyl 74 cytochrome c. J Biol Chem, 252(21), 7743-51, 1977.


Postdoctoral Position Available
No

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Updated Date
01/18/2012